The hematopoietic stem cells (HSC) in the adult bone marrow (BM) maintain hematopoiesis by virtue of their unique self-renewal capacity. The self-renewal of HSC is at the heart of BM transplantation, a life-saving procedure in many hematological diseases. Self-renewal appears fundamentally different from proliferation, and requires unique extrinsic signals and intrinsic transcriptional regulators. During the first award cycle, we have identified zinc finger transcription factor Zfx as a novel specific regulator of adult HSC maintenance. Recent evidence suggests that many leukemias are propagated by rare leukemic stem cells (LSC), whereas other leukemia types appear more uniformly aggressive. In either case, the fundamental driving force of leukemia, and a prime target for therapy, is uncontrolled or misplaced self-renewal by leukemic cells. The regulators of normal HSC self-renewal are often hijacked by leukemic cells including LSC to facilitate their self-renewal. Indeed, our preliminary results show that Zfx is required for leukemic cell development and/or propagation in several leukemia models. We propose that Zfx is an essential regulator of leukemic cell self-renewal, and as such represents an attractive candidate for future drug development. This hypothesis will be explored using three Specific Aims. First, the role of Zfx in the self-renewal of LSC population in vivo will be explored. Second, the requirement for Zfx in the propagation of aggressive leukemias without a distinct LSC compartment will be analyzed. The third Aim will focus on the molecular mechanism of Zfx activity and its target genes in transformed hematopoietic cells. Altogether, these studies would elucidate a novel genetic pathway regulating self-renewal of leukemic cells, and provide candidates for future development of rational therapeutic approaches against leukemia.